Advances in drug design, combinatorial synthetic chemistry, and high throughput screening methods have led to the discovery of thousands of drug candidates that can be used for treatment of life-threatening diseases such as inflammation, cancer, and AIDS. However, the majority (>95%) of these new molecules do not progress beyond the initial discovery phase to become clinically active therapies. The main hurdle facing their development into potent therapies with defined dosing regimen is the lack of effective formulation strategies that improve drug's aqueous solubility and stability, enhance its transport across epithelial and endothelial barriers encountered within the body, and allow selective drug accumulation and retention in diseased tissue and more specifically in the cytoplasm of targeted cells. One viable approach to overcome this challenge is to use biocompatible polymers as vehicles for targeted delivery of therapeutic molecules.
The use of polymers as carriers for pharmacologically active molecules started several decades ago, which eventually led to the development of different classes of polymeric drug delivery systems such as polymer-protein and polymer-drug conjugates, polymeric micelles, polyplexes, and supramolecular assemblies that are collectively known as “polymer therapeutics”. Several polymer-protein conjugates have matured beyond the exploration phase to reach routine clinical use for treatment of life-threatening diseases. These clinically-approved polymer-protein conjugates utilize a water-soluble polymer, polyethylene glycol (PEG), to shield protein drugs from the degrading enzymes present in the systemic circulation, reduce drug's renal clearance and increase its circulation residence time, and improve its overall biocompatibility.
Despite the merits of these systems, there is a critical need for more sophisticated polymer-drug conjugates that can actively recognize and selectively accumulate in diseased tissue, trigger specialized transport mechanisms to enter target cells, and produce a spatially- and temporally-controlled drug release in specific sub-cellular compartments. To address this need, the present invention provides for the development of novel enzyme-activated, nano-sized, polymer-drug conjugates (dendrimers) for targeted drug delivery.
Liver cancer is the fifth most common cancer in the world accounting for approximately one million new cases per year. The American Cancer Society estimated that 19,160 new cases would be diagnosed with primary liver cancer with approximately 16,780 deaths in 2007. Surgical resection of tumor tissue is considered a good treatment option, however, only 15%-30% of hepatic cancer patients are operative candidates and they typically exhibit a 30%-60% recurrence rate. Other treatment options include thermal and chemical ablation, chemoembolization, and regional and systemic chemotherapy. Unfortunately, these treatment strategies are highly invasive with limited specificity towards cancer cells and have failed to improve the survival of hepatic cancer patients, which remains less than 12 months. This clearly indicates the urgent clinical need for innovative drug delivery systems, which can selectively shuttle a high dose of anticancer drug molecules into hepatic cancer cells and achieve the desired cancer cell death. To address this unmet clinical need, the present invention provides polymer-drug conjugates for treatment of primary liver cancer particularly hepatocellular carcinoma (HCC).